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Integrin ?6?4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease.


ABSTRACT: To develop stem/progenitor cell-based therapy for cystic fibrosis (CF) lung disease, it is first necessary to identify markers of human lung epithelial progenitor/stem cells and to better understand the potential for differentiation into distinct lineages. Here we investigated integrin ?6?4 as an epithelial progenitor cell marker in the human distal lung. We identified a subpopulation of ?6?4(+) cells that localized in distal small airways and alveolar walls and were devoid of pro-surfactant protein C expression. The ?6?4(+) epithelial cells demonstrated key properties of stem cells ex vivo as compared to ?6?4(-) epithelial cells, including higher colony forming efficiency, expression of stem cell-specific transcription factor Nanog, and the potential to differentiate into multiple distinct lineages including basal and Clara cells. Co-culture of ?6?4(+) epithelial cells with endothelial cells enhanced proliferation. We identified a subset of adeno-associated virus (AAVs) serotypes, AAV2 and AAV8, capable of transducing ?6?4(+) cells. In addition, reconstitution of bronchi epithelial cells from CF patients with only 5% normal ?6?4(+) epithelial cells significantly rescued defects in Cl(-) transport. Therefore, targeting the ?6?4(+) epithelial population via either gene delivery or progenitor cell-based reconstitution represents a potential new strategy to treat CF lung disease.

SUBMITTER: Li X 

PROVIDER: S-EPMC3861522 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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Integrin α6β4 identifies human distal lung epithelial progenitor cells with potential as a cell-based therapy for cystic fibrosis lung disease.

Li Xiaopeng X   Rossen Nathan N   Sinn Patrick L PL   Hornick Andrew L AL   Steines Benjamin R BR   Karp Philip H PH   Ernst Sarah E SE   Adam Ryan J RJ   Moninger Thomas O TO   Levasseur Dana N DN   Zabner Joseph J  

PloS one 20131212 12


To develop stem/progenitor cell-based therapy for cystic fibrosis (CF) lung disease, it is first necessary to identify markers of human lung epithelial progenitor/stem cells and to better understand the potential for differentiation into distinct lineages. Here we investigated integrin α6β4 as an epithelial progenitor cell marker in the human distal lung. We identified a subpopulation of α6β4(+) cells that localized in distal small airways and alveolar walls and were devoid of pro-surfactant pro  ...[more]

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